Pivotal Trials in Ophthalmology: A Guide for Trainees 3030639770, 9783030639778

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Pivotal Trials in Ophthalmology A Guide for Trainees Jenny C. Dohlman Alice C. Lorch Editors

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Pivotal Trials in Ophthalmology

Jenny C. Dohlman  •  Alice C. Lorch Editors

Pivotal Trials in Ophthalmology A Guide for Trainees

Editors

Jenny C. Dohlman Department of Ophthalmology Massachusetts Eye and Ear Harvard Medical School Boston, MA USA

Alice C. Lorch Department of Ophthalmology Massachusetts Eye and Ear Harvard Medical School Boston, MA USA

ISBN 978-3-030-63977-8    ISBN 978-3-030-63978-5 (eBook) https://doi.org/10.1007/978-3-030-63978-5 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Introduction

Starting in residency and beyond, it is expected that ophthalmologists are well versed in the landmark clinical trials and research studies that have shaped the way in which ophthalmology is practiced today. Pivotal Trials in Ophthalmology: A Guide for Trainees is an introductory text designed to give trainees a comprehensive and accessible overview of important research trials across the subspecialties of ophthalmology and may also serve as a useful reference for practicing ophthalmologists, optometrists, and researchers in the field. Each chapter focuses on a different subspecialty and is authored by a chosen expert in the field, along with one or more trainees. Together, the authors of each chapter selected up to ten studies with which they feel every trainee and practicing ophthalmologist should be familiar; these are summarized and laid out in chronological order. Our hope is that by having trainees work closely with expert clinicians to produce this text, we have produced a resource that is detailed and accurate while remaining concise and accessible when questions arise in clinical practice, in studying for board examinations, or in designing future clinical trials. By including illustrated timelines of the sequence of these studies, we hope to demonstrate how studies have built upon prior knowledge and to depict visually how developments across subspecialties relate to one another.

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Introduction

Glaucoma AGIS

OHTS CIGTS EMGT

CNTGS

TVT

AVB

LiGHT PTVT

EAGLE

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Cornea Risk Factors for Graft Failure/Rejection. Histocompatibility Matching in Corneal Transplantation. HEDS-SKS HEDS-SKN

HEDS-EKT

HEDS-IRT

HEDS-APT

n-3 Fatty Acid Supplementation for DED Crosslinking for Keratoconus CPTS MUTT II

CDS SCUT MUTT I

HEDS-RFS

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018

Neuro-Ophthalmology MOG Optic Neuritis Tocilizumab in GCA

Sagging Eye Syndrome. ONTT

IONDT

EAGLE

H.I.N.T.S.

IIHTT

1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018

Pediatric Ophthalmology and Strabismus ETROP ATS2B ATS1

CRYO-ROP

Early Surgery for Infantile Esotropia. ATS3

Bilateral LR Recession vs. Unilateral Recess/Resect for Intermittent Exotropia.

IATS BEAT-ROP

CITT

1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

Retina EVS

CATT

DRCR.net Voretigene Protocol T. Neparvovec. VIEW Ozurdex DRCR.net 1 & 2 AREDS2 MEAD Protocol S. Argus II SCORE2

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

2014

2015 2016

2017

Uveitis SITE Difluprednate vs. Infliximab Prednisolone for MUST Refractory for Anterior Uveitis. Uveitis. HURON

SUN

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

VISUAL I, II and III.

SYCAMORE

Yutiq ®

POINT

2016

2017

2018

2019

FAST

Oculoplastics SPA: Age as a Factor in Bacteriology and Treatment Respons.

Selenium and Graves’ Orbitopathy.

Non-surgical Management of SPA.

ERIVANCE

STEVIE

Teprotumumab for TAO.

OPTIC

1994 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020

Ocular Trauma

1996

1997

1998

Delayed IOFB Removal without Endophthalmitis. CT in the Low Rate Diagnosis Vision of of Occult Survival Endophthalmitis OGIs. after OGI. in OGIs.

Prognostic Significance of Classifying Mechanical Injuries in OTS OGIs.

A Standardized Classifying Classification Mechanical of Ocular Injuries of Trauma. the Eye.

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

Poor Prognoses of OGIs with Concomitant Orbital Fractures.

Retinal Detachment after OGI.

2011

2012

2013

2014

2015

2016

2017

2018

2019

Contents

1 Glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .    1 Catherine M. Marando and Lucy Q. Shen 2 Cornea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  25 Kevin K. Ma and Jia Yin 3 Neuro-Ophthalmology . . . . . . . . . . . . . . . . . . . . . . . . .  43 Devon Ashley Cohen, Vivian Paraskevi Douglas, and Elizabeth Fortin 4 Pediatric Ophthalmology and Strabismus . . . . . . . . .  63 Marguerite C. Weinert and Gena Heidary 5 Retina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  89 Tedi Begaj, Ravi Parikh, and Dean Eliott 6 Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 Wen Fan Hu, Sanchay Gupta, and George N. Papaliodis 7 Oculoplastics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141 Edith R. Reshef and Suzanne K. Freitag 8 Ocular Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .155 Noam D. Rudnick and Matthew F. Gardiner Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171

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Contributors

Tedi Begaj, MD  Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA Devon  Ashley  Cohen, MD  Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA Vivian Paraskevi Douglas, MD, DVM, MBA  Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA Dean Eliott, MD  Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA Elizabeth Fortin, MD  Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA Suzanne  K.  Freitag, MD Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA Matthew  F.  Gardiner, MD Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA Sanchay  Gupta, BS Harvard Medical School, Boston, MA, USA

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Contributors

Gena  Heidary, MD, PhD Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA Wen  Fan  Hu, MD, PhD Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA Kevin  K.  Ma, MD Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA Catherine M. Marando, MD  Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA George  N.  Papaliodis, MD  Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA Ravi  Parikh, MD, MPH Manhattan Retina & Eye Consultants, New York, NY, USA Edith R. Reshef, MD  Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA Noam  D.  Rudnick, MD, PhD Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA Lucy  Q.  Shen, MD  Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA Marguerite C. Weinert, MD  Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA Jia  Yin, MD, PhD Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA

Chapter 1 Glaucoma Catherine M. Marando and Lucy Q. Shen

Abstract  Over the last 25  years, clinical trials in glaucoma have shaped modern clinical and surgical practice. Glaucoma is well suited to clinical trials given the relative prevalence in the community and the length of follow-up. This chapter briefly summarizes ten key trials that affect how we manage glaucoma today. Early trials explored the natural course of glaucoma and the importance of lowering intraocular pressure in primary open angle glaucoma, normal tension glaucoma, and ocular hypertension. More recent trials investigated the role of laser or filtering surgeries for primary open angle glaucoma and lens extraction for primary angle closure glaucoma.

C. M. Marando · L. Q. Shen (*) Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA e-mail: [email protected]; Lucy_Shen@meei. harvard.edu © The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 J. C. Dohlman, A. C. Lorch (eds.), Pivotal Trials in Ophthalmology, https://doi.org/10.1007/978-3-030-63978-5_1

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AGIS

C. M. Marando and L. Q. Shen

CNTGS

OHTS CIGTS EMGT

TVT

AVB

EAGLE

LiGHT PTVT

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

 he Advanced Glaucoma Intervention Study T (AGIS) – 1994 [1–5] Purpose To understand the clinical course after argon laser trabeculoplasty (ALT) and trabeculectomy in patients with advanced open angle glaucoma (OAG) that cannot be controlled on medications alone. Methods From 1988 to 1992, investigators at 11 clinical sites in the United States evaluated 789 eyes from 591 patients (56% black and 42% white) between the ages of 35 and 80  years. Patients were included if they had advanced glaucoma on maximum medical therapy and had elevated intraocular pressure (IOP), visual field (VF) defects and/or optic disc rim deterioration. Eyes were randomly assigned to receive one of two treatment sequences: ALT-trabeculectomy-­trabeculectomy (ATT) or trabeculectomy-ALT-­ trabeculectomy (TAT). Subjects would only receive the second or third treatments in the sequence if they demonstrated failure of the first treatment based on elevated IOP, visual field progression and/or optic disc rim deterioration. Visual acuity, visual fields and IOP were assessed three and six months after enrollment, and every six months thereafter. The primary outcome measures were changes in visual acuity and visual fields [1]. Results Data were reported over a 10-year follow-up period. Black patients had less visual field loss with the ATT sequence compared to the TAT sequence at four years, but did not show this difference for the following six years. However, black patients had significantly better visual acuity with the ATT sequence compared to the TAT sequence throughout the 10-year duration. On the other hand, white patients had less visual field

Chapter 1.  Glaucoma

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loss at 10 years with the TAT sequence compared to the ATT sequence. White patients had better visual acuity with the ATT sequence compared to the TAT sequence for the initial four years, but this was confounded by cataract formation [2]. Average IOP greater than 17.5  mmHg was associated with increased progression of visual field as compared to IOP less than 14 mmHg after six years of follow-up time [3]. Trabeculectomy, whether as the first or second intervention, increased risk for cataract formation by 78% [4]. Cataract formation did not alter the study conclusions recommending ATT in black patients and TAT in white patients [5]. In both black and white patients, the need for a second intervention was less in the TAT group (32% black; 18% white) as compared to the ATT group (50% both races). Both black and white patients required fewer topical glaucoma medications in the TAT group compared to ATT group [2]. Key Points • Based on visual field and visual acuity results, the ATT sequence was recommended for black patients and the TAT sequence was recommended for white patients for treatment of medically uncontrolled glaucoma. • At the time of the trial, the only topical therapies available were miotics, beta-blockers, epinephrine, and carbonic anhydrase inhibitors. ALT was offered because selective laser trabeculoplasty (SLT) was not yet available. • Trabeculectomy increased the risk for developing a visually significant cataract. • Elevated IOP, even less than 20  mmHg, was associated with increased progression of visual field defects. This led to the recommendation to further lower IOP for patients with advanced glaucoma.

 ollaborative Normal-Tension Glaucoma C Study (CNTGS) – 1998 [6–7] Purpose To evaluate the role of intraocular pressure (IOP) in normal tension glaucoma (NTG).

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Methods This randomized clinical trial conducted at 24 centers enrolled 230 patients with unilateral or bilateral NTG as evidenced by glaucomatous cupping of the disc, visual field loss, and a median IOP of 20 mmHg or less in 10 baseline measurements (following a four week washout period of any topical glaucoma medications). Patients were excluded if the pressure was ever recorded as greater than 24 mmHg. Subjects with a visual field defect threatening central fixation were ­immediately randomized, and all other patients were observed before randomization until they progressed either by visual field or optic disc criteria. Patients were then randomized to either observation or a 30% reduction in IOP by medical or surgical intervention. Beta-blockers and alpha agonists were not used due to the potential for confounding systemic effects. Two physicians independently confirmed optic disc progression based on disc photos. Visual field (VF) progression was based on defined criteria and the analysis was conducted both on defined VF endpoints and in a four-of-five analysis where progression needed to be confirmed on four-­ of-­five follow-up field tests. Patients were observed over 7 years of follow-up. Once progression was detected by optic disc and/or VF criteria, the subject could be treated at the primary clinician’s discretion regardless of treatment arm [6]. Results One hundred and forty-five subjects met criteria for randomization either by showing progression or having a threat to central fixation. Forty-six percent of patients were randomized to treatment and 56% were untreated controls. A threat to central fixation was present in 63% of untreated and 64% of treated patients. However, despite randomization, the baseline IOP was significantly higher in the treatment group than the control group (16.9 vs. 16.1 mmHg, p = 0.02). Using disc change or four-of-five visual field change as the combined endpoint, 30% of the untreated controls showed progression versus 18% of the treated patients. Over the 7-year follow-up period, the median survival time from randomization to progression was 2255  days for the treatment group

Chapter 1.  Glaucoma

5

versus 1837 days for the control group (p = 0.01). To account for increased cataract formation associated with filtering surgery, patients with visually significant cataracts were removed from the analysis. However, this disproportionately removed advanced glaucoma patients from the treatment arm [6]. Adjusted for other variables, the risk ratio for having progression in NTG patients based on visual field was 2.58 (p = 0.0058) for migraine, 2.72 (p = 0.0036) for disc hemorrhage, and 1.85 (p = 0.0622) for female gender [7]. Key Points • This study demonstrated the need for IOP lowering in normal tension glaucoma to prevent progression. • However, this was a controversial study given significant differences in baseline IOP between the treatment and observational arms, removal of patients with cataracts from the analysis, and other adjustments. • Over 7  years of follow-up, progression still occurred in 18% of patients despite treatment achieving a 30% reduction in IOP. Migraine, disc hemorrhage, and female gender were risk factors for rapid visual field progression in patients with NTG.

 he Collaborative Initial Glaucoma Treatment T Study (CIGTS) – 2001 [8–11] Purpose To determine if patients with newly diagnosed open angle glaucoma (primary, pigmentary, or pseudoexfoliative) are managed better with medications or immediate filtration surgery. Methods From 1993 to 1997, investigators at 14 clinical sites in the United States enrolled 607 patients aged 25–75  years with newly diagnosed open angle glaucoma. Patients were randomized to treatment with glaucoma medications (n  =  307) or

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trabeculectomy (n = 300). A target intraocular pressure (IOP) was established using a novel formula that takes into account baseline IOP and visual field (VF) score. Patients were followed at six-month intervals for up to 10  years. If a patient experienced treatment failure (based on specific IOP and VF criteria), then there was a crossover in treatment group. Specifically, failure of medical therapy would progress first to ALT and then to trabeculectomy. In the trabeculectomy arm, failure would progress to ALT and then medications. The primary outcome measure was progressive visual field loss evaluated by changes in mean deviation (MD). A substantial VF loss was defined as a decrease in MD of ≥3  dB.  Secondary outcomes included visual acuity and IOP [8]. Results By eight years, 21.3% of the surgery group and 25.5% of the medicine group showed worsening in VF from baseline. Subjects with worse MD at baseline, such as −10 dB, had better VF outcomes at five to nine years when treated initially with surgery as compared to medicine. Diabetic patients (n = 102) experienced less VF loss over the nine year follow­up period when treated with medical therapy first compared to trabeculectomy. IOP fluctuation over six baseline measurements was predictive of greater VF loss over the follow-­up period. Specifically, a range >8.5 mmHg had 96% greater odds of substantial VF loss [9]. Interestingly, at 5  years, 13.9% of patients showed an improvement in VF of ≥3 dB from baseline, which was associated with lower mean IOP, lower minimum IOP and lower sustained levels of IOP at follow-up [10]. Of the patients in the medication arm, self-reported compliance correlated negatively with VF progression, such that those who reported missing medications at two thirds of follow-­up visits had approximately 3.5 times the amount of visual field loss compared to those with perfect compliance at eight years [11]. Key Points • Initial treatment with either surgery or medicine, to achieve a target IOP calculated from baseline IOP and VF severity, produced similar rates of VF loss after eight years.

Chapter 1.  Glaucoma

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• At the initiation of the trial, effective medical treatments were limited and trabeculectomy was performed without antimetabolites. • For patients with moderate to advanced glaucoma at diagnosis, indicated by a lower mean deviation, initial surgery produced better long-term VF outcomes than medical treatment. • Diabetic patients did better with initial medical therapy rather than surgical treatment. • Baseline IOP fluctuation was correlated with VF progression at follow-up. • Better self-reported eye drop compliance was correlated with better VF outcomes.

 cular Hypertension Treatment Study O (OHTS) – 2001 [12–16] Purpose To evaluate the safety and efficacy of topical intraocular pressure (IOP) lowering medications in preventing glaucomatous damage in patients with ocular hypertension (OHTN). Methods This randomized controlled clinical trial was conducted at 22 centers and enrolled 1636 patients from 1994 through 1996. Subjects aged 40–80  years were included if the IOP was 24–32 mmHg in one eye and 21–32 mmHg in the fellow eye with normal gonioscopy, normal and reliable visual fields (VFs) and normal optic disc photos, which were graded by certified readers. Subjects were randomized to either close observation or topical pressure lowering medications, which were escalated in a stepwise fashion to reach a goal IOP of 20% below baseline and not exceeding 24 mmHg. The choice of medications was at the discretion of the treating physician. Patients were followed every six months with VFs and annual disc photos for a median of 72 months. VFs were considered abnormal if p 21 mmHg or less than 20% reduction from baseline, IOP ≤5 mm Hg, reoperation for glaucoma or loss of light perception vision [21]. Results The average study age was 71  years, 53% of subjects were female, 45% were white, and 39% were black. At follow-up years one and two, the tube group required significantly more glaucoma medications than the trabeculectomy group, how-

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ever there was no significance for the following three years. At five years, the Baerveldt implant produced a 41.4% reduction in IOP with mean IOP of 14.4 mmHg and the trabeculectomy with MMC produced a 49.5% reduction in IOP with mean IOP of 12.6  mmHg, although the difference was not statistically significant [22]. Early post-operative complications were significantly higher (p  =  0.012) in the trabeculectomy group (37%) than the tube group (21%). The rate of choroidal effusion was very similar between groups (13% trabeculectomy, 14% tube). The trabeculectomy group had higher rates of wound leak (11% trabeculectomy, 1% tube) and hyphema (8% trabeculectomy, 2% tube). At five years, late post-operative complications were similar between groups (36% trabeculectomy, 34% tube) [23]. There were more post-operative interventions in the trabeculectomy group (70%) than the tube group (25%). The most common post-operative procedures in the trabeculectomy group were laser suture lysis (55%), 5-FU injection (25%), and needling (13%). Four patients in the tube group and zero patients in the trabeculectomy group required anterior chamber reformation. The total number of reoperations for complications was similar between groups (18% trabeculectomy, 22% tube) [23]. Cumulative probability of treatment failure was significantly higher in the trabeculectomy group (46.9%) than the tube group (29.8%). The most notable difference in cause of treatment failure between groups was persistent hypotony (31% trabeculectomy, 13% tube), which was defined as IOP ≤5  mmHg on two consecutive follow-up visits after three months [22]. Key Points • Both nonvalved tube surgery and trabeculectomy effectively lowered IOP in patients with previous intraocular surgery. • Early post-operative complications were more likely in the trabeculectomy group than the tube group.

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• Late post-operative complications were similar between groups. • Treatment failure occurred more frequently with trabeculectomy, in large part due to persistent hypotony.

 he Ahmed Versus Baerveldt Study (AVB) – T 2011 [24–27] Purpose To compare the Ahmed and Baerveldt aqueous drainage devices for the treatment of refractory glaucoma. Methods This randomized clinical trial conducted at seven international clinical sites enrolled 238 patients from 2005 to 2009. Patients 18 or older were included if they had inadequately controlled glaucoma despite medical, laser and/or surgical therapy and were planned to receive an aqueous drainage device. Patients were randomized to an Ahmed-FP7 valve or a Baerveldt-350 implant. Patients were followed postoperatively at defined intervals up to five years. The primary outcome was failure, defined as follows: intraocular pressure (IOP)  18  mmHg or IOP reduction 18  mmHg,

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which occurred in 56% of the Ahmed group and 26% of the Baerveldt group. Hypotony resulted in 4% of failures in the Baerveldt group, but none in the Ahmed group (p = 0.02) [26]. Both groups had similar IOP within nine months of surgery [25], but subsequently the mean IOP was significantly lower in the Baerveldt group than the Ahmed group (13.6 mmHg vs. 16.6 mmHg at five years, p = 0.001) [26]. The Baerveldt group required significantly fewer medications at all visits from follow-up month two through year five [26]. At three years, 25% of the Ahmed group and 50% of the Baerveldt group required no medications (p